A systematic analysis of protein kinases in malaria parasites to identify, validate and prioritise novel drug targets

Lead Research Organisation: The Wellcome Trust Sanger Institute
Department Name: Research Directorate

Abstract

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Technical Summary

Malaria is a major infectious disease of man, with 500 million clinical cases thought to result in more than one million deaths each year. In the absence of a licensed vaccine, the emergence of resistance to available drugs continues to be a serious problem. There is a sustained need for new, affordable drugs that contrasts starkly with the level of investment pharmaceutical companies allocate to the problem. In view of limiting resources, the validation and prioritisation of potential drug targets is particularly important. The large family of protein kinases encoded in the parasite‘s genome is of particular interest for drug target identification, because members of the kinase family have in the past been shown to play key essential function in the parasite‘s life cycle progression. The aim of the research programme proposed here is to identify, validate and prioritise the most promising target kinases encoded in the parasite‘s genome and to study their biological functions in parasite development and transmission. In the proposal we define the essential and desirable properties of parasite protein kinases that qualify as high priority targets and suggest six experimental filters, which we will use to evaluate candidate kinases. On the one hand our analysis will initially look at members of a family of calcium-dependent protein kinases, for which we have already assembled a strong body of evidence suggesting their suitability as targets. On the other hand, we propose a multidisciplinary and collaborative approach that will combine the genetic tractability of Plasmodium berghei, a malaria parasites infecting rodents, and bioinformatics, biochemical and structural studies on protein kinases of P. falciparum, to carry out an unbiased, genome-wide analysis of Plasmodium protein kinases with the aim of identifying novel, high priority targets for pharmacological intervention.

Publications

10 25 50
 
Title Parasite 
Description 'Parasite' has been created by artist Deborah Robinson working in close collaboration with Wellcome Trust Sanger Institute malaria researchers Oliver Billker and Julian Rayner. During a residency at the Sanger Institute, Deborah explored how genomics is being used to understand the biology of the parasite that causes malaria and how this may be used to establish new ways of preventing or treating the disease. For this exhibition Deborah has used sections of archival films which she found within the Wellcome Collection and Imperial War Museum Library and which depict the 'mass eradication' campaigns which characterised attempts to control the disease in the last century. She deploys software, developed with digital and sound artist David Strang, to corrode sections of this archival documentary footage and reminding us of the cyclical and recurrent nature of this deadly disease. This project was funded by Arts Council England and was displayed at the Ruskin Gallery in the Cambridge School of Art at Anglia Ruskin University until 18 July 2013. 
Type Of Art Film/Video/Animation 
Year Produced 2013 
Impact Talks about Parasite have taken place at: Inspace (Bio informatics gallery), Edinburgh University; Tent Gallery, Edinburgh University; St John's College, Cambridge; Exeter University. In 2013 Parasite was selected for inclusion in the Shanghai International Science and Art exhibition where it won an award for excellence in Science and Art. Solo exhibitions featuring Parasite have taken place at the Ruskin Gallery, Cambridge, July 2013, ICIA, University of Bath, March 2014. Heidelberg Castle, Germany, May 2014 (sponsored by The European Virtual Institute of Malaria Research and EVIMalaR). 
URL http://www.sanger.ac.uk/about/engagement/art.html
 
Description Consultation - Malaria Eradication Research Agenda (malERA) initiative, Washington, USA
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Consultation - Medicines for Malaria Venture: Kinase Workshop, London
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Consultation - NIH/Gates Gametocyte Biology, Bethesda, USA
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Consultation - WT: Next Steps for Plasmodium Post-genomic Research - A Strategy Meeting
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Title PlasmoGEM resource and database 
Description To scale up the systematic genetic validation of malaria drug and vaccine targets we initiated the Plasmodium Genetic Modification Project, PlasmoGEM. We first made significant improvements to the genetic system of Plasmodium berghei, a model parasite infecting rodents, by overcoming the challenges of manipulating large fragments of AT-rich parasite DNA in E. coli. This enabled us to develop a production pipeline for highly efficient genetic modification vectors at genome scale, which uses recombinase mediated engineering of parasite genomic libraries (Pfander et al., Nature Methods, 2011). In 2012 we started the production and free dissemination of a community resource of genetic modification tools for P. berghei, which is supported by a public database ( http://plasmogem.sanger.ac.uk) . PlasmoGEM project is based to a large part on concepts that result directly from the MRC Senior Fellowship Award, which also provided the PI salary. The grant also funded pilot studies, as well as proof of principle experiments applying PlasmoGEM vectors to parasite protein kinases. The PlasmoGEM resource itself and its further development is supported by a core grant from the Wellcome Trust to the Sanger Institute. It is a joint project with Dr. Julian Rayner at the Institute. 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact The PlasmoGEM project will bring about a step change in the genetic validation of drug and vaccine targets in P. berghei. The project has the potential to unite the research community around the opportunity of systematic reverse genetics studies on a global scale. Importantly, and as additional genetic tools are being developed, the PlasmoGEM resource will increase the throughput of genetic studies by several orders of magnitude, enabling for the first time the experimental analysis of global gene-environment and gene-drug interactions in a malaria parasite. 
URL http://plasmogem.sanger.ac.uk
 
Description Christian Doerig 
Organisation Wellcome Trust
Department Wellcome Trust Centre for Molecular Parasitology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution P. berghei mutants/phenotyping. Also jointly reviewed literature on protein kinase signalling in Plasmodium. Currently jointly supervising PhD student. We also collaborate through 2 FP-7 networks.
Collaborator Contribution Expertise/Collaboration on P. falciparum signalling mutants
Impact PMID: 19839262, 19491095, 18845480, see also publications reported for previous grant.
 
Description Imperial College Drug Discovery 
Organisation Imperial College London
Department Department of Chemistry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Target identifcation, protein expression, biological expertise, biological assays.
Collaborator Contribution Drug development expertise, staff, drug screen
Impact Drug screen has produced leads. Lead refinement in progress.
Start Year 2007
 
Description Jane Endicott 
Organisation University of Oxford
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Functional analysis of CDPK family of protein kinases.
Collaborator Contribution Structural Biology Expertise
Impact Wellcome Trust Project Grant to study CDPK structure.
Start Year 2006
 
Description William Snell 
Organisation University of Texas Southwestern Medical Center
Country United States of America 
Sector Academic/University 
PI Contribution William Snell identified candidate gamete fusion factor in Chlamydomonas. My team collaborated with Snell and Sinden (Imperial College London) on functional analysis in Plasmodium.
Collaborator Contribution Identification of gamete fusion portein
Impact Patent application filed for transmission blocking malaria vaccine. PMID 18367645
Start Year 2006
 
Description Parasite 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Parasite, joint project with Julian Rayner and Deborah Robinson, visiting artist.

First exhibit Anglia Ruskin University 06/2013. Plan for future exhibits in 2014.
Year(s) Of Engagement Activity 2013
URL http://www.deborah-robinson.net/parasite